Despite 35 years of clinical trials, there has been little improvement in five-year survival rates with any chemotherapeutic regimen for the treatment of metastatic melanoma. Here, we demonstrate a previously unrecognized role for Abl kinases in melanoma cells. We found that c-Abl/Arg non-receptor tyrosine kinases are activated in primary melanomas and in melanoma cell lines, and promote proliferation, survival, cell-cell adhesion, migration, invasion, and lung colonization/metastasis. In addition, c-Abl/Arg promote matrigel invasion via STAT3 and MMP-dependent pathways; increase cell-cell adhesion; and dramatically induce degradation of a metastasis suppressor. Moreover, drugs targeting c-Abl/Arg and Raf/MEK/ERK pathways cooperate to decrease melanoma viability. Based on these novel findings, we hypothesize that c-Abl/Arg activate novel pathways that cooperate with B-Raf to promote melanoma cell-cell adhesion, migration, invasion, and metastasis. We propose a comprehensive hypothesis-driven experimental design that will establish Abl kinases as novel and exploitable drug targets for metastatic melanoma. Aim 1 will define molecular pathways by which Abl kinases promote cell-cell adhesion, migration, and invasion. To achieve our objective, we will combine biochemical, molecular, and cell biological approaches using RNAi, pharmacological inhibitors, constitutively active forms of c-Abl/Arg, rescue experiments, 2D/3D cell culture, and melanoma- endothelial co-cultures to identify migration, invasion, and cell-cell adhesion signaling pathways driven by c- Abl/Arg. Aim 2 will test the prediction that c-Abl/Arg cooperates with Abl-independent pathways (e.g. B-Raf) to promote melanoma cell-cell, adhesion, migration, and invasion. Finally, three complementary approaches will be utilized in Aim 3 to identify mechanisms by which c-Abl/Arg promote metastasis. A novel GEM model that develops metastatic UV-induced melanomas, and lung colonization and spontaneous metastasis xenograft models will be used to test the prediction that blocking c-Abl/Arg-dependent signaling pathways inhibits metastatic progression. We also will test whether B-Raf and c-Abl/Arg inhibitors cooperate to prevent metastasis of melanomas harboring B-Raf mutations. The data obtained from this proposal not only will allow us to gain insight into the fundamental mechanisms by which c-Abl/Arg drive invasion and metastasis, but also will lead to clinical studies testing the efficacy of c-Abl/Arg inhibitors for treating metastatic disease.